DESCRIPTION: The goals of our proposal are to bring together an expert team of bioengineers and stem cell/developmental biologists to create a Human Islet Biomimetic that will facilitate (i) long term culture and manipulation of human islets and (ii) maturation of stem-cell derived or reprogrammed islets. Specifically, we will combine our expertise in cell and developmental biology with our experience molding three dimensional vascularized scaffolds in which cellular inputs, matrix composition, and microscale organization (including flow) can be varied with precision. Although much is known about islet function under homeostatic conditions in vivo, current methods for studying islet physiology and pathophysiology are severely limited. Studies that rely on model organisms - particularly mice - are hampered by cellular and molecular discrepancies between human and rodent islets. The use of human islets for studies of islet physiology is also problematic, as limited availability and exposure to non-physiological conditions during isolation impede the use of this cellular source. Most importantly, there is no system currently available which supports the full function of islets or b-cells for more than a fe days in culture. Thus, our understanding of islet function and dysfunction - particularly as it relates to type 1 diabetes (T1D) - has been constrained by the lack of tools for maintaining and studying human islets in vitro. Into this gap, we will take cadaveric human islets, pancreatic progenitors from human ES and iPS cells, and endocrine cells that are trans-differentiated from intestinal stem cells as starting material, and incorporate them into innovative scaffold devices that provide control over local structure, cellular content, and fluid dynamics to stabilize b-cell function. Overall, we plan to reconstitute human islet biomimetics that recapitulate the diverse cellular types and their organization within the natural human islet. In addition, we will use the system to explore the reasons why islets are prone to lose function when placed ex vivo and to model human islet diseases. This system will be critical for the success of other HIRN consortia, as well for the b-cell biology community at large by providing an accessory system for studying b-cell survival, immune interactions, and alternate sources of b-cells. Our Aims are as follows: Aim 1: To establish a human islet biomimetic for sustained islet viability and function in vitro. Aim 2: To optimize human islet biomimetic function with respect to glucose sensing, insulin release, and stable maintenance of islet phenotypes. Our study is designed to provide a deeper understanding of the molecular and cellular events that lead to islet dysfunction in T1D and related islet disorders and to help develop strategies to restore normal islet function in these disorders.